Tags

Type your tag names separated by a space and hit enter

Thromboxane synthase inhibitors suppress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets: role of adenylylcyclase up-regulation.
J Pharmacol Exp Ther. 1995 Dec; 275(3):1497-505.JP

Abstract

Exposure of human platelets to U46619, a thromboxane (Tx) A2 mimetic, desensitizes the TxA2/prostaglandin (PG) H2 receptor and sensitizes adenylylcyclase to stimuli, such as PGI2 or PGD2. This phenomenon may occur in vivo in conditions associated with platelet activation. Tx synthase inhibitors produce a rediversion of arachidonic acid metabolism toward the adenylylcyclase stimulators PGD2 and PGI2. We assessed whether the desensitization of the platelet TxA2 receptor affects the antiplatelet activity of drugs acting on the arachidonic acid metabolic cascade. A Tx synthase inhibitor (OKY046), a PGH2/TxA2 receptor antagonist (BM13.505), their combination, two dual Tx synthase inhibitors/receptor antagonists (picotamide and ridogrel) or the cyclooxygenase inhibitor aspirin were studied. OKY046 alone or combined with BM13.505, picotamide and ridogrel, as well as PGD2, but not BM13.505 or aspirin, caused a stronger inhibition of platelet aggregation with desensitized platelets; this effect was potentiated by the phosphodiesterase inhibitor HL725 and was almost abolished by the adenylylcyclase inhibitor SQ22,536. A larger increase in cAMP synthesis was observed in desensitized as compared with control platelets with a Tx synthase inhibitor or with dual Tx synthase inhibition/receptor antagonism. No differences were observed in the degree of TxA2 suppression. Our observations showed that Tx synthase inhibitors exerted a stronger antiaggregatory effect in TxA2 receptor-desensitized platelets due to a stimulation of adenylylcyclase. This can be of relevance in the treatment of thrombotic disorders in which an in vivo desensitization of platelet TxA2 receptors takes place.

Authors+Show Affiliations

Institute of Internal and Vascular Medicine, University of Perugia, Italy.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8531121

Citation

Vezza, R, et al. "Thromboxane Synthase Inhibitors Suppress More Effectively the Aggregation of Thromboxane Receptor-desensitized Than That of Normal Platelets: Role of Adenylylcyclase Up-regulation." The Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 3, 1995, pp. 1497-505.
Vezza R, Nenci GG, Gresele P. Thromboxane synthase inhibitors suppress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets: role of adenylylcyclase up-regulation. J Pharmacol Exp Ther. 1995;275(3):1497-505.
Vezza, R., Nenci, G. G., & Gresele, P. (1995). Thromboxane synthase inhibitors suppress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets: role of adenylylcyclase up-regulation. The Journal of Pharmacology and Experimental Therapeutics, 275(3), 1497-505.
Vezza R, Nenci GG, Gresele P. Thromboxane Synthase Inhibitors Suppress More Effectively the Aggregation of Thromboxane Receptor-desensitized Than That of Normal Platelets: Role of Adenylylcyclase Up-regulation. J Pharmacol Exp Ther. 1995;275(3):1497-505. PubMed PMID: 8531121.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thromboxane synthase inhibitors suppress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets: role of adenylylcyclase up-regulation. AU - Vezza,R, AU - Nenci,G G, AU - Gresele,P, PY - 1995/12/1/pubmed PY - 1995/12/1/medline PY - 1995/12/1/entrez SP - 1497 EP - 505 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 275 IS - 3 N2 - Exposure of human platelets to U46619, a thromboxane (Tx) A2 mimetic, desensitizes the TxA2/prostaglandin (PG) H2 receptor and sensitizes adenylylcyclase to stimuli, such as PGI2 or PGD2. This phenomenon may occur in vivo in conditions associated with platelet activation. Tx synthase inhibitors produce a rediversion of arachidonic acid metabolism toward the adenylylcyclase stimulators PGD2 and PGI2. We assessed whether the desensitization of the platelet TxA2 receptor affects the antiplatelet activity of drugs acting on the arachidonic acid metabolic cascade. A Tx synthase inhibitor (OKY046), a PGH2/TxA2 receptor antagonist (BM13.505), their combination, two dual Tx synthase inhibitors/receptor antagonists (picotamide and ridogrel) or the cyclooxygenase inhibitor aspirin were studied. OKY046 alone or combined with BM13.505, picotamide and ridogrel, as well as PGD2, but not BM13.505 or aspirin, caused a stronger inhibition of platelet aggregation with desensitized platelets; this effect was potentiated by the phosphodiesterase inhibitor HL725 and was almost abolished by the adenylylcyclase inhibitor SQ22,536. A larger increase in cAMP synthesis was observed in desensitized as compared with control platelets with a Tx synthase inhibitor or with dual Tx synthase inhibition/receptor antagonism. No differences were observed in the degree of TxA2 suppression. Our observations showed that Tx synthase inhibitors exerted a stronger antiaggregatory effect in TxA2 receptor-desensitized platelets due to a stimulation of adenylylcyclase. This can be of relevance in the treatment of thrombotic disorders in which an in vivo desensitization of platelet TxA2 receptors takes place. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/8531121/Thromboxane_synthase_inhibitors_suppress_more_effectively_the_aggregation_of_thromboxane_receptor_desensitized_than_that_of_normal_platelets:_role_of_adenylylcyclase_up_regulation_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8531121 DB - PRIME DP - Unbound Medicine ER -